The present invention relates to compounds having biological activity as cholecystokinin ligands, to pharmaceutical compositions employing these compounds, and to a method of employing the pharmaceutical compositions in a method of treatment.
More particularly, this invention concerns 2-substituted-[2-substituted-amino]-N-arylalkyl-3-[indol-3-yl]propanamides having demonstrated activity at the central cholecystokinin receptor, with pharmaceutical compositions containing these compounds, and with a method of inhibiting appetite employing the pharmaceutical compositions.
The cholecystokinin (CCK) peptides are widely distributed in various organs of the body including the gastrointestinal tract, endocrine glands, and in the nerves of the peripheral and central nervous systems. Various biologically active forms have been identified including a 33-amino acid hormone and various carboxyl-terminus fragments of this peptide (e.g. the octapeptide CCK.sub.26-33 and the tetrapeptide CCK.sub.30-33). (See G. J. Dockray, Br. Med. Bull., 38:, (No. 3): 253-258 (1982)).
The various CCK peptides are thought to be involved in the control of smooth muscle contractility, exocrine and endocrine gland secretion, sensory nerve transmission, and numerous brain functions. Administration of the native peptides causes gall bladder contraction, amylase secretion, excitation of central neurones, inhibition of feeding, anticonvulsive actions and other behavioral effects (See "Cholecystokinin: Isolation, Structure and Functions," G. B. J. Glass, Ed., Raven Press, New York, 1980, pp. 169-221; J. E. Morley, Life Sciences, 27: 355-368 (1980); "Cholecystokinin in the Nervous System," J. de Belleroche and G. J. Dockray, Ed , Ellis Horwood, Chichester, England, 1984, pp. 110-127.
The high concentrations of CCK peptides in many brain areas also indicate major brain functions for these peptides (see G. J. Dockray, Br. Med. Bull., 38 (No. 3): 253-258 (1982)). The most abundant form of brain CCK found is CCK.sub.26-33, although smaller quantities of CCK.sub.30-33 exist (see Rehfeld and Gotterman, J. Neurochem., 32: 1339-1341). The role of central nervous system CCK is not known with certainty, but it has been implicated in the control of feeding. (See Della-Fera and Baile, Science, 206: 471-473. )
Currently available appetite suppressant drugs either act peripherally by increasing energy expenditure (such as thyroxine), or in some other manner (such as the biguanides), or act by exerting a central effect on appetite or satiety.
Centrally acting appetite suppressants either potentiate central catecholamine pathways, and tend to be stimulants (for example amphetamine), or influence serotonergic pathways (for example fenfluoramine). Other forms of drug therapy include bulking agents which act by filling the stomach, thereby inducing a "feeling" of satiety